O R I G I N A L A R T I C L E – T H O R A C I C O N C O L O G Y
Quality of Life During and After Completion of Neoadjuvant
Chemoradiotherapy for Esophageal and Junctional Cancer
B. J. Noordman, MD, PhD1, M. G. E. Verdam, PhD2, B. Onstenk, MD, MSc1, J. Heisterkamp, MD, PhD3, W. J. B. M. Jansen, MSc3, I. S. Martijnse, MD, PhD3, S. M. Lagarde, MD, PhD1, B. P. L. Wijnhoven, MD, PhD1, C. M. M. Acosta, BSc1, A. van der Gaast, MD, PhD4, M. A. G. Sprangers, MD, PhD2, and
J. J. B. van Lanschot, MD, PhD1
1
Department of Surgery, Erasmus MC – University Medical Centre Rotterdam, Rotterdam, The Netherlands;2Department of Medical Psychology, Academic Medical Centre, Amsterdam, The Netherlands;3Department of Surgery, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands;4Department of Medical Oncology, Erasmus MC – University Medical Centre Rotterdam, Rotterdam, The Netherlands
ABSTRACT
Background. The course of health-related quality of life (HRQOL) during and after completion of neoadjuvant chemoradiotherapy (nCRT) for esophageal or junctional carcinoma is unknown.
Methods. This study was a multicenter prospective cohort investigation. Patients with esophageal or cancer to be treated with nCRT plus esophagectomy were eligible for inclusion in the study. The HRQOL of the patients was measured with European Organization for Research and Treatment of Cancer C30, OG25, and QLQ-CIPN20 questionnaires before and during nCRT, then 2, 4, 6, 8, 10, 12, 14, and 16 weeks after nCRT and before surgery. Predefined end points were based on the hypoth-esized impact of nCRT. The primary end points were physical functioning, odynophagia, and sensory symptoms. The secondary end points were global quality of life, fatigue, weight loss, and motor symptoms. Mixed modeling analysis was used to evaluate changes over time.
Results. Of 106 eligible patients, 96 (91%) were included in the study. The rate of questionnaires returned ranged
from 94% to 99% until week 12, then dropped to 78% in week 16 after nCRT. A negative impact of nCRT on all HRQOL end points was observed during the last cycle of nCRT (all p \ 0.001) and 2 weeks after nCRT (all p\ 0.001). Physical functioning, odynophagia, and sen-sory symptoms were restored to pretreatment levels respectively 8, 4, and 6 weeks after nCRT. The secondary end points were restored to baseline levels 4–6 weeks after nCRT. Odynophagia, fatigue, and weight loss improved after nCRT compared with baseline levels at respectively 6 (p \ 0.001), 16 (p = 0.001), and 12 weeks (p \ 0.001). Conclusion. After completion of nCRT for esophageal cancer, HRQOL decreases significantly, but all HRQOL end points are restored to baseline levels within 8 weeks. Odynophagia, fatigue, and weight loss improved 6–16 weeks after nCRT compared with baseline levels.
Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is a standard of care for patients with potentially curable esophageal or esophagogastric junctional cancer.1,2 Although esophagectomy has a profound impact on both long- and short-term patient health-related quality of life (HRQOL), addition of nCRT to surgery does not jeopar-dize HRQOL after surgery compared with surgery alone.3,4 However, immediately after completion of nCRT (before surgery), patients show a profound drop in HRQOL com-pared with baseline levels.3,5,6This deterioration improves after surgery, suggesting that HRQOL is restored in the period between completion of nCRT and surgery.3,5 However, the detailed course of HRQOL during and after
Electronic supplementary material The online version of this article (https://doi.org/10.1245/s10434-019-07779-w) contains supplementary material, which is available to authorized users.
Ó The Author(s) 2019
First Received: 20 January 2019
B. J. Noordman, MD, PhD e-mail: b.noordman@erasmusmc.nl https://doi.org/10.1245/s10434-019-07779-w
completion of nCRT is unknown. Such information might have an impact on the timing of surgery, although this is debated. Traditionally, surgery is scheduled 4–6 weeks after completion of nCRT. However, findings have shown that a longer time to surgery (up to 12 weeks) does not endanger oncologic outcome.7 Increasing the time to sur-gery allows patients to recover from nCRT and optimize their physical condition before surgery. Furthermore, a longer waiting time to surgery is suggested to increase the pathologically complete response rate (i.e., no viable tumor cells in the resection specimen), which might improve prognostication.7
This study aimed primarily to assess the course of HRQOL in the period from the start of nCRT until surgery for patients with locally advanced esophageal or junctional carcinoma.
METHODS
A multicenter prospective cohort study was conducted. Patients with locally advanced esophageal or esophago-gastric junctional cancer, as determined by endoscopic ultrasound, computed tomography (CT) and/or positron emission tomography (PET)-CT, who would be undergoing nCRT according to the ChemoRadiotherapy for Oesopha-geal cancer followed by Surgery Study (CROSS) regimen (weekly administration of carboplatin and paclitaxel plus 41.4-Gy concurrent radiotherapy) were considered eligible for the study.1Patients considered insufficiently fluent in the Dutch language or cognitively unable to understand the questionnaire were excluded. Consecutive patients were recruited before the start of nCRT in the Erasmus MC– University Medical Centre, Rotterdam, and in the Elisa-beth-Tweesteden Hospital, Tilburg. The study was approved by the ethics committee of the Erasmus MC (MEC-2016-250).
HRQOL Measurement
Patients were informed about the study by their own physician. Subsequently, patients were asked to participate via telephone by one of the investigators. Participating patients received the self-report questionnaires by mail and were asked by telephone to complete the questionnaire at baseline (before nCRT), at the date of the last nCRT cycle, and every 2 weeks thereafter until the date of surgery, with a maximum follow-up period of 16 weeks after completion of nCRT. All the patients completed the questionnaires themselves and were reminded twice via telephone by one of the investigators during each assessment.
Cancer-related general HRQOL was measured with the European Organization for Research and Treatment of
Cancer (EORTC) QLQ-C30, a validated questionnaire for cancer patients.8Esophageal cancer-specific HRQOL was assessed with the EORTC QLQ-OG25, a validated ques-tionnaire for patients with cancer of the esophagus, the esophago-gastric junction, and the stomach.9 Chemother-apy-induced peripheral neuropathy (CIPN) symptoms were assessed using the EORTC QLQ-CIPN20, a questionnaire designed to elicit patients’ experience of symptoms related to CIPN.10
Before the start of the study, end points were defined by individual consensus discussion with upper gastrointestinal (GI) surgical oncologists, medical oncologists, and nurse practitioners. One primary end point and one or two sec-ondary end points from each questionnaire were chosen based on the hypothesized impact of nCRT. This led to assignment of physical functioning (EORTC QLQ-C30), odynophagia (EORTC QLQ-OG-25), and sensory symp-toms (EORTC QLQ-CIPN20) as primary end points, and to global quality of life, fatigue (both QLQ-C30), weight loss (EORTC QLQ-OG25), and motor symptoms (EORTC QLQ-CIPN20) as secondary end points.
Statistical Analysis
Data were analyzed on an intention-to-treat basis. Pre-treatment clinicopathologic characteristics were collected and described. Questionnaire scores were transformed into a 0–100 scale according to EORTC guidelines.11 Higher scores for functional and global scales (e.g., physical functioning and global quality of life) indicate better HRQOL. Higher scores on symptom scales (e.g., fatigue) indicate worse HRQOL.
Over-time changes in the follow-up measurements were analyzed using mixed modeling analysis, a technique that enables analysis of all completed questionnaires by allowing for inclusion of data from patients with different numbers of completed measurements.12 Mean over-time differences were described.
Cohen’s d (CD) effect sizes based on the beta estimates from the mixed modeling analyses were used to allow for standardized comparison between different end points and to assess clinical relevance of the found effects. The CD values of 0.2, 0.5, and 0.8 indicate small, medium, and large effects, respectively.13 Effect sizes of 0.5 or larger were defined as clinically relevant.14
On an exploratory basis, we investigated the effects of several background variables on the trajectory of HRQOL scores. Because the investigated sample showed variation in timing of surgery, this could have influenced the course of HRQOL.
Some patients (n = 29) participated in the diagnostic preSANO trial.15,16 In that trial, the patients underwent a clinical response evaluation (CRE) using endoscopy with
biopsies, endoscopic ultrasound, and PET-CT 4–6 weeks after nCRT to determine the accuracy of residual disease detection. The patients with residual disease or non-pass-able tumor during the clinical response evaluation after 4–6 weeks underwent immediate surgical resection, whereas the remaining patients had surgery 10–14 weeks after completion of nCRT.
Patients with (substantial) residual disease after nCRT might experience worse HRQOL after nCRT, which potentially induces a bias. Furthermore, variations in time to surgery can be attributed to patient-related characteris-tics such as comorbidities or general condition. More vulnerable patients could have a longer time until surgery intentionally. This might negatively influence HRQOL at longer follow-up measurements, so HRQOL may improve more strongly at the later measures if all patients could have been included. Therefore, the study included the presence of residual disease during clinical response eval-uation (only for patients who participated in the preSANO trial), comorbidities (Charlson Comorbidity Index), the American Society of Anesthesiology (ASA) score, age, gender, histology, and cT stage in a separate analysis to investigate their potential effect on the course of HRQOL.17
As a correction for multiple comparisons, a p value lower than 0.006 was considered statistically significant (a Bonferroni correction of 0.05/9 was applied because the main analyses included nine comparisons with pretreat-ment levels). All p values were two-sided. Data were analyzed using SPSS version 24.0 (IBM, Chicago, IL, USA).
RESULTS
Of 106 eligible patients, 96 (91%) were included from May 2016 through June 2017 (10 patients refused partici-pation). The rates of response to the questionnaires ranged from 78 to 99% (Table1). The median age of the patients was 68 years (interquartile range [IQR], 61–71 years), and
TABLE 1 Eligibility status of the study patients Status Baseline Last
cycle 2 Weeks 4 Weeks 6 Weeks 8 Weeks 10 Weeks 12 Weeks 14 Weeks 16 Weeks Eligible 96 96 96 96 93 88 56 49 42 32
Total returned questionnaires (% of eligible) 95 (99) 90 (94) 93 (97) 92 (96) 89 (96) 83 (94) 51 (91) 46 (94) 37 (88) 25 (78) Surgery (cumulative) 0 0 0 0 3 8 39 46 53 63 Deceased 0 0 0 0 0 0 1 1 1 1 Too ill 0 4 1 1 1 1 1 1 3 4 Randomly missing/other 1 2 2 3 3 4 4 2 2 3 TABLE 2 Clinicopathologic characteristics of the study patients Characteristic (n = 96)
n (%) Age at inclusion (years)
Median 68
IQR 61–71
Male sex 77 (80)
Tumor type
Squamous cell carcinoma 18 (19) Adenocarcinoma 78 (81) Clinical T stagea cT1 1 (1) cT2 15 (16) cT3 77 (80) cT4 3 (3) Clinical N stageb cN0 33 (34) cN1 38 (4) cN2 19 (20) cN3 6 (6) ASA classificationc 1 15 (16) 2 65 (68) 3 14 (15) Missing 2 (2)
IQR interquartile range, ASA American Society of Anesthesiology
aClinical tumor (cT) stage was assessed via endoscopic
ultrasonog-raphy or computed tomogultrasonog-raphy (CT) and classified according to the International Union for Cancer Control (IUCC) tumor-node-metas-tasis (TNM) classification, 7th ed
bClinical lymph-node (N) stage was assessed via endoscopic
ultra-sonography, CT, or 18F-fluorodeoxyglucose positron-emission tomography and classified according to IUCC TNM classification, 7th ed
cASA classification is on a scale of 0 to 5, with lower numbers
indicating better physical status, 1 indicating a normal healthy patient, 2 indicating a patient with mild systemic disease, and 3 indicating a patient with severe systemic disease
77 (80%) of the patients were men. Most of the patients had cT3 tumor (80%) and suspicious regional lymph nodes (66%; Table2).
Predefined Primary End Points
Physical Functioning (Fig.1a) The over-time changes in physical functioning levels were statistically significant (p \ 0.001). Physical functioning had declined at the last cycle of nCRT (- 16; p \ 0.001; CD - 0.80; 95% 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 pretr eatment last cycle nCR T
2 weeks4 weeks6 weeks8 weeks10 weeks12 weeks14 weeks16 weeks
pretr eatment
last cycle nCR T
2 weeks4 weeks6 weeks8 weeks10 weeks12 weeks14 weeks16 weeks
pretr eatment
last cycle nCR T
2 weeks4 weeks6 weeks8 weeks10 weeks12 weeks14 weeks16 weeks
pretr eatment
last cycle nCR T
2 weeks4 weeks6 weeks8 weeks10 weeks12 weeks14 weeks16 weeks pretr
eatment
last cycle nCR T
2 weeks4 weeks6 weeks8 weeks10 weeks12 weeks14 weeks16 weeks pretr
eatment
last cycle nCR T
2 weeks4 weeks6 weeks8 weeks10 weeks12 weeks14 weeks16 weeks pretr
eatment
last cycle nCR T
2 weeks4 weeks6 weeks8 weeks10 weeks12 weeks14 weeks16 weeks
Physical functioning scor
e
Odynopahgia scor
e
Sensory symptoms scor
e
Global quality of life scor
e
Fatigue scor
e
W
e
ight loss scor
e Motor symptoms scor er a b c d e f g
FIG. 1 Mean scores with standard deviations for aphysical functioning, bodynophagia, c sensory symptoms (primary end points), dglobal quality of life, efatigue, f weight loss, and gmotor symptoms (secondary end points)
confidence interval [CI], - 1.00 to - 0.59) compared with the baseline levels. During the follow-up period, physical functioning improved from 2 to 10 weeks after nCRT (4 vs 2 weeks: ? 6; p \ 0.001; CD 0.30; 95% CI 0.17–0.42; 6 vs 4 weeks: ? 6; p \ 0.001; CD 0.28; 95% CI 0.17–0.39; 8 vs 6 weeks: ?5; p \ 0.001; CD 0.24; 95% CI 0.15–0.32; 10 vs 8 weeks: ? 3; p = 0.003; CD 0.15; 95% CI 0.05–0.24, respectively). From this point, the improvement was no longer statistically significant. Baseline levels were reached at 8 weeks (p = 0.95) but were not exceeded during the follow-up period.
Odynophagia (Fig.1b) The over-time changes in odynophagia levels were statistically significant (p \ 0.001). Compared with the baseline levels, the odynophagia levels had worsened at the last cycle of nCRT (14; p \ 0.001; CD - 0.45; 95% CI 0.20–0.70) and remained at that level 2 weeks after nCRT (p = 0.038). Thereafter, the odynophagia levels improved from 2 to 4 weeks (- 21; p \ 0.001; CD - 0.69; 95% CI - 0.89 to - 0.49), and from 4 to 6 weeks (- 11; p \ 0.001; CD - 0.37; 95% CI - 0.50 to - 0.24). After that, improvement was no longer statistically significant compared with the previous measurement. At 4 weeks after nCRT, baseline levels were reached (p = 0.68), and at 6 weeks, the odynophagia levels had improved compared with baseline levels (6 weeks: - 15; p \ 0.001; CD - 0.42; 95% CI - 0.64 to - 0.20; 10 weeks: - 24; p\ 0.001; CD - 0.77; 95% CI - 0.98 to - 0.57). Sensory Symptoms (Fig.1c) Generally, the over-time changes in sensory symptoms were not statistically significant (p = 0.009). However, the specific comparisons between occasions showed that sensory symptoms had worsened at the last cycle of nCRT compared with pretreatment levels, (?4: p \ 0.001; CD 0.53; 95% CI 0.28–0.80). At 6 weeks after nCRT, sensory symptoms had returned to baseline levels (p = 0.013). No further statistically significant improvement compared with previous measurements was observed.
Predefined Secondary End Points
Global Quality of Life (Fig.1d) The global quality-of-life scores showed statistically significant changes over time (p \ 0.001). At the last cycle of nCRT, the global quality-of-life scores had declined (- 16: p \ 0.001; CD - 0.77; 95% CI - 0.96 to - 0.57) and had further worsened 2 weeks thereafter (- 6: p = 0.002; CD - 0.29; 95% CI - 0.47 to - 0.11). From 2 to 8 weeks after nCRT, the global quality-of-life levels improved compared with the previous measurement (4 vs 2 weeks: ? 11; p \ 0.001; CD 0.51; 95% CI 0.33–0.69; 6 vs
4 weeks: ? 7; p \ 0.001; CD 0.34; 95% CI 0.19–0.49; 8 vs 6 weeks: ? 5; p = 0.001; CD 0.24; 95% CI 0.10–0.39, respectively). After that, improvement was no longer statistically significant. At 6 weeks after nCRT, baseline levels were reached (p = 0.031). The baseline levels were not exceeded during the follow-up period.
Fatigue (Fig.1e) Over time, the fatigue levels changed significantly (p \ 0.001). Compared with baseline, the fatigue levels had increased at the last cycle of nCRT (? 34: p \ 0.001; CD 1.21; 95% CI 1.04–1.39) and remained stable until 2 weeks after nCRT (p = 0.32). After that, improvement was observed until 6 weeks compared with the previous measurements (4 vs 2 weeks: - 15; p \ 0.001; CD - 0.57; 95% CI - 0.73 to - 0.41; 6 vs 4 weeks: - 13; p \ 0.001; CD - 0.46; 95% CI - 0.60 to - 0.32). Baseline levels were reached at 6 weeks (p = 0.007). Thereafter, no statistically significant improvement compared with the previous measurement was observed. Compared with baseline levels, improvement was observed 16 weeks after nCRT (- 8; p = 0.001; CD - 0.28; 95% CI - 0.44 to - 0.11). Weight Loss (Fig.1f) The weight loss scores changed significantly over time (p \ 0.001). At the last cycle of nCRT, weight loss had worsened compared with baseline levels (? 10: p = 0.002; CD 0.36; 95% CI 0.13–0.58) and did not improve 2 and 4 weeks after nCRT compared with the previous measurement (p = 0.263 and 0.038, respectively). The scores then returned to baseline levels 4 weeks after nCRT (p = 0.031) and improved further (6 vs 4 weeks: 9; p \ 0.001; CD - 0.31; 95% CI - 0.47 to - 0.16; 8 vs 6 weeks: - 7; p \ 0.001; CD - 0.24; 95% CI - 0.37 to - 0.12). At 12 weeks after nCRT, the weight loss scores had improved compared with baseline levels (- 15; p \ 0.001; CD - 0.52; 95% CI - 0.79 to - 0.26). Motor Symptoms (Fig.1g) The over-time change in motor symptoms was statistically significant (p \ 0.001). Motor symptoms had worsened at the last cycle of nCRT (? 4; p \ 0.001). At 4 weeks after nCRT, the motor symptoms had returned to baseline levels (p = 0.028). No further improvements in motor symptoms compared with previous measurements was observed.
Other End Points The mean scores of HRQOL domains, except for the predefined end points, are presented in Table3.
Influence of Residual Disease, Comorbidities, and General Condition Inclusion of residual disease present during the clinical response evaluation, comorbidities (Charlson
Comorbidity Index), ASA score, age, gender, histology, and cT stage as control variables did not have an impact on the reported overall trends in HRQOL trajectories (data not shown). However, the patients who had residual disease during CRE exhibited worse odynaphagia levels. The patients with higher Charlson Comorbidity Index (CCI) experienced more fatigue, and the patients with a higher cT stage had more weight loss (Table S1). Furthermore, the patients who had residual disease during CRE or a higher
ASA score had increased weight loss over time (Table S2; Fig. S1).
DISCUSSION
This prospective cohort study showed a profound neg-ative, short-term impact of nCRT on all HRQOL end points for patients who had esophageal or junctional cancer treated with a multimodality regimen based on carbo-platin/paclitaxel combined with 41.4 Gy of concurrent
TABLE 3 Mean scores for all domains in the three European Organization for Research and Treatment of Cancer (EORTC) questionnaires that were not predefined end points
Status Baseline Last cycle 2 Weeks 4 Weeks 6 Weeks 8 Weeks 10 Weeks 12 Weeks 14 Weeks 16 Weeks QLQ-C30 Functional scales Role 82 ± 23 56 ± 32 50 ± 32 26 ± 30 71 ± 27 79 ± 23 81 ± 22 81 ± 25 82 ± 25 85 ± 25 Emotional 75 ± 20 74 ± 24 72 ± 23 78 ± 19 80 ± 20 81 ± 17 81 ± 19 83 ± 16 82 ± 17 82 ± 19 Cognitive 91 ± 16 81 ± 25 82 ± 20 86 ± 19 91 ± 16 92 ± 16 91 ± 17 93 ± 14 93 ± 13 95 ± 12 Social 88 ± 18 70 ± 30 69 ± 27 78 ± 23 86 ± 20 88 ± 18 89 ± 18 89 ± 18 90 ± 19 91 ± 18 Symptom scores
Nausea and vomiting 12 ± 23 28 ± 30 32 ± 32 13 ± 20 10 ± 19 5 ± 15 3 ± 8 5 ± 11 5 ± 11 1 ± 3 Pain 14 ± 19 32 ± 28 38 ± 31 22 ± 26 14 ± 20 11 ± 20 12 ± 22 11 ± 21 12 ± 24 9 ± 19 Dyspnea 8 ± 16 20 ± 26 22 ± 26 20 ± 26 12 ± 21 11 ± 21 11 ± 21 13 ± 19 11 ± 19 8 ± 15 Insomnia 27 ± 30 35 ± 33 33 ± 34 24 ± 31 20 ± 25 16 ± 24 18 ± 24 17 ± 26 14 ± 20 12 ± 25 Loss of appetite 21 ± 28 46 ± 35 52 ± 35 33 ± 34 18 ± 26 12 ± 24 12 ± 22 12 ± 24 11 ± 21 7 ± 17 Constipation 9 ± 21 25 ± 33 25 ± 32 13 ± 24 7 ± 16 5 ± 14 7 ± 15 4 ± 13 4 ± 10 7 ± 17 Diarrhea 6 ± 17 16 ± 26 15 ± 26 5 ± 16 4 ± 12 5 ± 13 7 ± 13 3 ± 9 4 ± 13 5 ± 12 Financial worries 3 ± 12 8 ± 22 6 ± 18 5 ± 14 5 ± 17 5 ± 16 4 ± 16 4 ± 13 4 ± 10 4 ± 11 QLQ-OG25 Symptom scores Dysphagia 27 ± 25 41 ± 28 56 ± 30 25 ± 25 16 ± 19 13 ± 21 10 ± 17 6 ± 12 6 ± 15 4 ± 7 Eating 42 ± 28 57 ± 28 62 ± 28 40 ± 31 27 ± 28 20 ± 27 16 ± 23 13 ± 20 10 ± 17 9 ± 15 Reflux 9 ± 18 14 ± 23 16 ± 26 8 ± 21 5 ± 14 3 ± 10 3 ± 12 3 ± 11 1 ± 6 1 ± 7 Pain and discomfort 15 ± 23 29 ± 28 30 ± 32 22 ± 28 14 ± 23 13 ± 22 10 ± 1912 7 ± 17 7 ± 17 10 ± 20 Anxiety 52 ± 25 46 ± 26 47 ± 27 43 ± 25 41 ± 27 43 ± 26 42 ± 26 41 ± 22 39 ± 26 36 ± 27 Eating with others 27 ± 33 34 ± 35 36 ± 26 21 ± 30 11 ± 24 7 ± 17 5 ± 12 5 ± 14 4 ± 10 1 ± 7 Dry mouth 13 ± 23 26 ± 28 29 ± 30 17 ± 24 13 ± 20 9 ± 20 12 ± 21 13 ± 27 9 ± 22 7 ± 14 Trouble with taste 18 ± 32 44 ± 37 46 ± 35 32 ± 32 21 ± 27 12 ± 24 10 ± 20 8 ± 20 5 ± 12 7 ± 17 Trouble swallowing saliva 13 ± 27 24 ± 32 24 ± 30 14 ± 26 7 ± 18 5 ± 15 3 ± 11 3 ± 12 2 ± 8 3 ± 9 Choking when swallowing 10 ± 22 9 ± 17 9 ± 18 5 ± 14 3 ± 10 4 ± 13 2 ± 9 4 ± 13 5 ± 14 3 ± 9
Trouble with coughing 26 ± 26 32 ± 28 34 ± 28 28 ± 27 21 ± 23 23 ± 24 19 ± 24 19 ± 25 17 ± 22 16 ± 17 Trouble talking 6 ± 18 10 ± 19 13 ± 24 8 ± 18 3 ± 10 3 ± 11 5 ± 13 4 ± 13 4 ± 10 4 ± 11 Hair loss 10 ± 25 22 ± 29 19 ± 26 21 ± 29 19 ± 31 16 ± 26 14 ± 28 14 ± 31 17 ± 36 5 ± 13 QLQ-CIPN20
Autonomic scale 11 ± 15 21 ± 19 22 ± 19 18 ± 18 14 ± 16 14 ± 15 14 ± 15 14 ± 16 14 ± 18 14 ± 18 Scores are presented as means ± standard deviations
radiotherapy. Subsequently, all primary and secondary HRQOL end points were restored to baseline levels 4–10 weeks after completion of nCRT. The odynophagia, fatigue, and weight loss scores even improved after nCRT compared with baseline levels at 6, 16, and 12 weeks, respectively.
This is the first study to investigate the detailed short-term course of HRQOL after nCRT for esophageal or junctional cancer. A previous study showed a negative impact of nCRT on HRQOL 12 weeks after the start of neoadjuvant treatment, which was restored to baseline levels 3 weeks before surgery.6However, this earlier study used a small sample (n = 34), only two measurements after nCRT with respect to the start of nCRT rather than the end of nCRT, and the date of surgery, hampering precise assessment of the HRQOL trajectory after nCRT. A study using the Functional Assessment of Cancer Therapy-Eso-phageal (FACT-E) demonstrated findings similar to those in the current study in terms of return to baseline before surgery, but included only patients who had neoadjuvant chemotherapy.18
The HRQOL analysis in the CROSS trial also showed a profound deterioration 1 week after completion of nCRT compared with baseline scores for all primary and sec-ondary HRQOL end points (physical functioning, global quality of life, fatigue, eating, and emotional functioning). However, this study lacked extra measurements between the end of nCRT and the date of surgery.3
The results of the current study underscore the value of sufficient recuperation time between completion of nCRT and esophagectomy to enable patients to undergo surgery in optimal physical condition, potentially improving sur-gical outcome. Moreover, delayed surgery tends to increase the pathologically complete response rate, potentially improving prognosis.7,19 We recommend that timing of surgery be guided by the patient’s condition. It is advo-cated that surgery be postponed to as long as 12 weeks after completion of nCRT, and even longer than that when patients experience persisting adverse events or are in bad general condition, especially in the absence of residual disease.
Previous studies have shown lasting deterioration of HRQOL after multimodality treatment for patients with esophageal cancer.4,20–22 Given the current results, these negative findings likely are attributable to esophagectomy and not to chemoradiotherapy per se. Definitive chemora-diotherapy without esophagectomy circumvents the adverse effects of surgery. However, the long-term onco-logic outcome is suggested to be inferior to (nCRT plus) surgery.23
An active surveillance strategy after completion of nCRT is a topic of investigation in the ESOSTRATE and Surgery As Needed for Oesophageal cancer (SANO)
trials.15,24 With this novel treatment strategy, patients undergo frequent clinical examinations after completion of nCRT, and esophagectomy is offered only to patients with a histologically proven or highly suspected locoregional regrowth without signs of distant dissemination. This active surveillance strategy might reduce the number of patients who need esophagectomy by 30–40%, reducing the impact of surgery on HRQOL. The results of the cur-rent study can be used to inform patients for whom a future active surveillance strategy is considered because the stable HRQOL levels during the last measurements likely reflect the HRQOL levels during active surveillance.
The limitations of the current study included the dif-ferences in timing of surgery between patients, which introduced different follow-up periods between patients. Nevertheless, inclusion of the confounders, namely, the presence of residual disease during clinical response eval-uation (only patients in the preSANO trial), comorbidities (Charlson Comorbidity Index), and ASA score, did not influence the overall trends in HRQOL trajectories.
Another limitation was the potential effect of response shift or reconceptualization of symptoms during treatment (i.e., what was bad before is the new normal). Unfortu-nately, this is inevitable in HRQOL studies.
In conclusion, HRQOL decreased substantially after completion of nCRT for esophageal cancer, but was restored to baseline levels for all end points within 10 weeks. Odynophagia, fatigue, and weight loss had improved within 16 weeks after nCRT compared with baseline levels. These results suggest a benefit of delaying surgery, especially for vulnerable patients, and can be used to inform patients for whom a future active surveillance strategy is considered.
DISCLOSURE There are no conflicts of interest.
OPEN ACCESS This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://crea tivecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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